The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system (CNS), and is involved in a variety of neuroendocrine and neurobehavioral processes. Evidence from animal models, postmortem tissues, and molecular neuroscience studies suggests that dysfunction of 5-HT2CR has been implicated in a number of significant neurological and psychiatric disorders, and 5-HT2CR has been identified as a target for the treatment of obesity, depression, anxiety, drug abuse, schizophrenia and Parkinson's disease. The unmet need is our inability to establish a direct relationship between 5-HT2CR physiology and brain diseases by accurately quantifying 5-HT2CR density and functional status in vivo using Positron Emission Tomography (PET), because there are no selective and specific PET radiotracer agonists or antagonists available for 5-HT2CR. The central objective of this proposal is to develop a carbon-11 5-HT2CR- specific radioligand antagonist with pharmacological and physiochemical properties for in vivo imaging studies by PET. The central hypothesis of this proposal is that a carbon-11 labeled bispyridyl-carbamoylindole derivative will enable mapping of both active and the resting states of 5-HT2C in a highly specific and sensitive manner. This hypothesis is based upon recent published reports and our preliminary findings on the excellent in vitro binding profiles of potent and selective 5-HT2CR antagonists, bispyridyl-carbamoylindoles. The central hypothesis will be tested by completing the following specific aims: 1. To synthesize and in vitro characterize bispyridyl-carbamoylindole derivatives. 2. To develop radiolabeling methods for the candidate 5-HT2CR ligand antagonist. 3. To determine whether radiolabeled candidate compounds will cross the blood brain barrier and the in vivo kinetic biodistribution in Sprague-Dawley rats is sufficient for quality PET imaging of 5-HT2CR. 4. To determine whether the lead candidate PET ligands show favorable distribution and kinetic properties for in vivo quantification of 5-HT2CR density in the brain of non-human primates.